Stimulus-Based Extinction Generalization: Neural Correlates and Modulation by Cortisol

Abstract

Background: While healthy individuals and patients with anxiety disorders easily generalize fear responses, extinction learning is more stimulus specific. Treatments aiming to generalize extinction learning are urgently needed, since they comprise the potential to overcome stimulus specificity and reduce relapses, particularly in the face of stressful events.

Methods: In the current 3-day functional magnetic resonance imaging fear conditioning paradigm, we aimed to create a generalized extinction memory trace in 60 healthy men and women by presenting multiple sizes of 1 conditioned stimulus during extinction training (CS+G; generalized), whereas the other conditioned stimulus was solely presented in its original size (CS+N; nongeneralized). Recall was tested on the third day after pharmacological administration of either the stress hormone cortisol or placebo.

Results: After successful fear acquisition, prolonged activation of the amygdala and insula and deactivation of the ventromedial prefrontal cortex for CS+G compared with CS+N during extinction learning indicated sustained fear to the generalization stimuli. In line with our hypotheses, reduced amygdala activation was observed after extinction generalization on the third day in the contrast CS+G minus CS+N, possibly reflecting an attenuated return of fear. Cortisol administration before recall, however, blocked this effect.

Conclusions: Taken together, the findings show that extinction generalization was associated with decreased activation of the fear network during recall after prolonged activation of the fear network during extinction learning. However, the generalization of the extinction memory did not counteract the detrimental effects of stress hormones on recall. Thus, stimulus-based extinction generalization may not be sufficient to reduce relapses after stressful experiences.

Keywords: Fear conditioning; functional magnetic resonance imaging; glucocorticoids; return of fear; stress hormones.

Figure 1.

Extinction generalization paradigm. The 3 phases (fear acquisition training, extinction training, and recall) were performed on 3 consecutive days with less than a 2-hour shift. Lightning bolts represent electrical stimulation as unconditioned stimulus in reinforced conditioned stimulus (CS+) trials (62.5% partial reinforcement) during fear acquisition training. In total, there were 8 presentations of each of the 3 CS on each day, which were adjusted according to the number of versions for each geometrical shape. Thus, during extinction training, each of the 4 versions of the CS+G (generalized) was only presented 2 times, whereas the CS+N (nongeneralized) and the non-reinforced conditioned stimulus (CS−) was presented 8 times each. Accordingly, each of the 2 versions of each CS were presented 4 times during recall. The CS distribution was equal over the course of each phase with the restriction of no more than 2 consecutive trials of the same CS.

Figure 2.

Differential neural responding for the contrast generalized extinguished conditioned stimulus (CS+G) minus non-generalized extinguished conditioned stimulus (CS+N) during extinction training. The slices were selected according to peak voxels of the activated ROI: (a) left amygdala, (b) vmPFC, and (c) right insula. Data are presented on the standard MNI brain template and thresholded to T ≥ 1 (see color bar for exact T values). Boxplots represent contrast estimates of the respective peak voxel (with black dots representing the mean). Abbreviations: A, anterior; L, left; P, posterior; R, right. During the first half of extinction training, increased activation of the left amygdala accompanied by decreased activation of the ventromedial prefrontal cortex (vmPFC) was observed for CS+G minus CS+N. In the second half of extinction training, right insula activation was increased for CS+G compared with CS+N.

Figure 3.

Differential neural responding for generalized extinguished conditioned stimulus (CS+G) minus non-generalized extinguished conditioned stimulus (CS+N) during recall. The slices were selected according to peak voxels of the activated ROIs: (a) left amygdala and (b) right parahippocampal gyrus (PHG). Functional connectivity between the right PHG and (c) the left hippocampus (T = 4.02, P = .015) is displayed. Data are presented on the standard MNI brain template and thresholded to T ≥ 1 (see color bar for exact T values). Boxplots represent contrast estimates of the respective peak voxel (with black dots representing the mean). Abbreviations: A, anterior; L, left; P, posterior; R, right. During recall, both the left amygdala and right PHG show a decreased activation to CS+G compared with CS+N.

Figure 4.

Cortisol effects on recall for the contrast generalized extinguished conditioned stimulus (CS+G) minus non-generalized extinguished conditioned stimulus (CS+N). The slices were selected according to peak voxels of the activated ROIs: (a) left amygdala and (b) left insula. Additionally, functional connectivity between the left insula and (c) the ventromedial prefrontal cortex (vmPFC) (T = 2.72, P = .046) is displayed. Data is presented on the standard MNI brain template and thresholded to T ≥ 1 for activations and T ≥ 2.5 for functional connectivity (see color bar for exact T values). Boxplots represent contrast estimates of the respective peak voxel (with black dots representing the mean). Abbreviations: A, anterior; L, left; P, posterior; R, right. Increased differential neural responding was present for CS+G minus CS+N for the cortisol compared with the placebo group.

Figure 5.

Neural model of extinction generalization based on the current findings. Extinction generalization results in prolonged fear expression reflected in amygdala and insula activation and delayed safety signaling in the ventromedial prefrontal cortex (vmPFC) during extinction training. Successful extinction generalization is mirrored in reduced amygdala activation and thus return of fear. Plus symbols indicate upregulation while minus symbols indicate downregulation of the respective area.